My long-term career goal is to become a successful independent scientist contributing to our understanding of skeletal development in order to improve human craniofacial health. A two-fold career development plan is described in this application including (1) a substantial career mentorship component and (2) expanding my research in new scientific directions. The proposed research tests hypotheses addressing two exciting new concepts regarding skeletal cells, extending my already substantial body of postdoctoral work in the laboratory of Dr. Charles Kimmel. The first aspect of my mentorship plan is the addition of another senior scientist as a co-mentor, Dr. John Postlethwait, providing fresh insight as I prepare for independence. As part of a complementary mentorship plan, Dr. Kimmel, Dr. Postlethwait and myself will meet monthly, in addition to my weekly meetings with Dr. Kimmel. Further mentorship will occur in the form of an Advisory Committee consisting of the University of Oregon faculty Dr. Judith Eisen (Neuroscience), Dr. Raghu Parthasarathy (Physics), and Dr. Kryn Stankunas (Molecular Biology), in addition to Drs. Kimmel and Postlethwait. I will meet biannually with the diverse group of scientists in my Advisory Committee following a presentation of my work to the broader University of Oregon research community. These meetings will have the following formal agendas: early award strategic planning, mid-course correction, job application planning, and transition to independence. The third portion of my mentorship will be my participation in the Institute of Neuroscience Assistant Professor Mentorship Program. This program provides mentees guidance with scientific writing, and lab management skills. The program is normally reserved for assistant professors in the institute and it is an honor that Dr. Shawn Lockery, the institute director, invited me to participate. The second tier of my career development plan involves a transition into several new areas of research including the fields of genomics & bioinformatics, as well as mouse developmental biology. These new directions will complement my existing expertise in cell biology and biochemistry from graduate school, and zebrafish developmental genetics from my postdoctoral studies. A segue into two new fields of study will require excellent training and I have a systematic plan in place to foster both of these transitions. To learn genomics & bioinformatics, I will work closely with my co-mentor that is an innovator in the field, and attend courses in the Bioinformatics Applied Masters program at the University of Oregon. So that I may translate my zebrafish studies into the mouse system, I will combine a formal intensive laboratory course in mouse development with training in the labs of two different mouse developmental biologists. Learning the mouse system is an integral part of my plan to bridge the gap between my zebrafish work, and human disease. The long-term outcome of this synergistic approach will be profoundly more impactful science when I combine all of these approaches in my own laboratory. The hypotheses tested in the research portion of this proposal address two new ideas about cells in the skeleton. First, I propose that a progenitor cell makes a series of binary cell fate choices resulting in the diversity of skeletal cell types. Second, I propose the oe gene away hypothesis as a means to understand how closely related skeletal cells are to each other. In this proposal, I focus on a hypothetical binary, cell autonomous choice to become either a ligament or a bone cell (Aim 1). I address how this cell fate choice is influenced by genetics and epigenetics (Aim 2). I will translate my zebrafish findings into the mouse model, linking my discoveries in the zebrafish to mammals (Aim 3). This work will impact our understanding of human craniofacial diseases involving ligaments and bones, such as Eagle's syndrome. The combination of careful planning, thorough mentorship, and innovative science proposed in this K99/R00 are certain to provide me with a pathway to independence.